3. INTRODUCTION
• Idiopathic pulmonary fibrosis (IPF) a.k.a
cryptogenic fibrosing alveolitis, is a specific form
of chronic, progressive fibrosing interstitial
pneumonia of unknown cause,
– primarily occurring in older adults,
– limited to the lungs,
– associated with histopathologic and/or radiologic
pattern of usual interstitial pneumonia (UIP)
• IPF portends a poor prognosis
• No proven effective therapies are available for its
treatment beyond lung transplantation.
4. INTODUCTION2
• IPF is an interstitial lung disease (ILD)
• ILDs represent a large number of conditions that
involve the parenchyma of the lung—the alveoli,
the alveolar epithelium, the capillary
endothelium, and the spaces between these
structures, as well as the perivascular and
lymphatic tissues.
• Heterogeneous group of disorders classified
together because of similar clinical,
roentgenographic, physiologic, or pathologic
manifestions
5. CLASSIFICATION
• ILD can be broadly classified based on major
histo-pathological finding into
(1) those associated with predominant inflammation
and fibrosis and
(2) those with a predominantly granulomatous
reaction
• Each can be subdivided into
– Known cause
– Unknown cause
6. Inflammation/Fibrosis
Known Cause
• Asbestosis
• Fumes, gases
• Drugs (antibiotics,
amiodarone, gold) and
chemotherapy drugs
• Radiation
• Aspiration pneumonia
• Residual of acute
respiratory distress
syndrome
• Smoking-related
– Desquamative interstitial
pneumonia (DIP)
– Respiratory bronchiolitis–
associated interstitial lung
disease
– Langerhans cell
granulomatosis
(eosinophilic granuloma of
the lung)
9. Granulomatous
Known Cause
• Hypersensitivity
pneumonitis (organic
dusts)
• Inorganic dusts:
beryllium, silica
• Unknown cause
• Bronchocentric
granulomatosis
• Lymphomatoid
granulomatosis
• Sarcoidosis
• Granulomatous
vasculitides
• Langerhans' cell
granulomatosis
• Wegener's
granulomatosis
• Allergic granulomatosis of
Churg-Strauss
10. EPIDEMIOLOGY
• IPF is the commonest of all Idiopathic Interstitial
Pneumonias (IIPs)
• Worldwide incidence
– 10.7 cases per 100,000 person-years for males and 7.4
cases per 100,000 person years for females.
• Worldwide prevalence
– 20 cases per 100,000 persons for males and 13 cases
per 100,000 persons for females.
• Kim DS, Collard HR, King TE., Jr Classification and natural history of the idiopathic interstitial pneumonias. Proc Am Thorac
Soc 2006;3:285–92.
11. EPIDEMIOLOGY
USA
• Age and sex adjusted incidence
– 8.8-17.4 per 100,000 person-years a
• Prevalence
– 27.4-63/100,000 person years a
• Nigeria – case reportb
• a-Fernandez Perez ER, Daniels CE, Schroeder DR, et al. Incidence, prevalence, and clinical course of idiopathic pulmonary fibrosis: a population-based study. Chest. Jan 2010;137(1):129-37
• b-A rare case of cor pulmonale secondary to idiopathic pulmonary fibrosis in Nigeria Raphael Chinedu Anakwue et al
12. EPIDEMIOLOGY
• Age
– >50yrs
• Sex prevalence
– >M:F (55yrs and older)
• Raghu G, Weycker D, Edelsberg J, Bradford WZ, Oster G. Incidence and prevalence of
idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. Oct 1 2006;174(7):810-6
13. AETIOLOGY
• Remains undefined
• However, some inciting agents have been
implicated
– Cigarette smoking
– Smoke
– Environmental pollutants
– Viral infections
– Gastroesophageal reflux disease
– Chronic aspiration
– Genetic basis : <5%
14. PATHOGENESIS
• Previous theory - generalized inflammation progressed
to widespread parenchymal fibrosis.
• Current theory - IPF is an epithelial-fibroblastic
disease, in which unknown endogenous or
environmental stimuli disrupt the homeostasis of
alveolar epithelial cells, resulting in diffuse epithelial
cell activation and aberrant epithelial cell repair.
Re-establishing an intact epithelium following injury is
a key component of normal wound healing.
15. PATHOGENESIS
• In IPF, exposure to an inciting agent in a
susceptible host may lead to the initial alveolar
epithelial damage
• Following injury, aberrant activation of alveolar
epithelial cells leading to
– 1) release of potent fibrogenic cytokines and growth
factors, eg. TNF-α, TGF-β, platelet-derived growth
factor, insulin-like growth factor-1, ET-1
– These are involved in the migration and proliferation
of fibroblasts and the transformation of fibroblasts
into myofibroblasts
16. PATHOGENESIS
– 2) provokes the
migration, proliferation,
and activation of
mesenchymal cells with
the formation of
fibroblastic/myofibroblas
tic foci
– myofibroblasts secrete
extracellular matrix
proteins
17. PATHOGENESIS
• Failure of apoptosis leads to myofibroblast
accumulation, exuberant extracellular matrix
protein production, persistent tissue
contraction, and pathologic scar formation
18. PATHOGENESIS
• TGF-β has been shown to promote an
antiapoptotic phenotype in fibroblasts
• Research has shown that apoptosis resistance
in the fibroblasts and myofibroblasts
participating in the repair of the alveolar
epithelium may contribute to the persistent
and/or progressive fibrosis in idiopathic
pulmonary fibrosis.
19. PATHOGENESIS
Genetic basis
– Mutant telomerase
• Telomerase is a specialized polymerase that
adds telomere repeats to the ends of
chromosomes, helping to offset shortening
that occurs during DNA replication.
• TGF-β negatively regulates telomerase
activity- mutation
20. PATHOGENESIS
• This telomere shortening could promote the
loss of alveolar epithelial cells, resulting in
aberrant epithelial cell repair, and therefore
should be considered as another potential
contributor to the pathogenesis of idiopathic
pulmonary fibrosis
21. PATHOGENESIS
– MUC5B
– Mucin 5B is a protein that is encoded MUC5B gene
• A common variant in the putative promoter of the
gene that encodes mucin 5B (MUC5B) has been
associated with the development of both familial
interstitial pneumonia and sporadic pulmonary fibrosis.
• MUC5B expression in the lung was reported to be 14.1
times as high in subjects who had idiopathic
pulmonary fibrosis as in those who did not.
• Therefore, dysregulated MUC5B expression in the lung
may be involved in the pathogenesis of pulmonary
fibrosis.
22. PATHOGENESIS
– Surfactant protein C
• Genetic mutations in serum surfactant protein
C have been discovered in some individuals
with familial pulmonary fibrosis.
• These mutations in serum surfactant protein
C may damage type II alveolar epithelial cells
23. PATHOGENESIS
– Caveolin-1
• Caveolin-1 limits TGF-β–induced production of
extracellular matrix proteins and restores the
alveolar epithelial-repair process.
• It has been observed that the expression of
caveolin-1 is reduced in lung tissue from
patients with idiopathic pulmonary fibrosis.
24.
25. CLINICAL FEATURES
• SYMPTOMS
• Gradual onset, often
greater than 6 months,
of dyspnea – exertional,
progressive
• and/or a nonproductive
cough
Systemic symptoms
(uncommon)
• Weight loss
• Low-grade fevers
• Fatigue
• Arthralgias
• Myalgias
26. CLINICAL FEATURES
• Approximately 5% of patients are
asymptomatic at diagnosis – routine chest
radiograph/lung biopsy
• In these group however, symptoms developed
approximately 1000 days after the recognition
of the radiographic abnormality a
• a-Kim DS, Collard HR, King TE Jr. Classification and natural history of the idiopathic interstitial
pneumonias. Proc Am Thorac Soc. Jun 2006;3(4):285-92.
27. CLINICAL FEATURES
• It is critical to obtain a complete history, including
– medication history – amiodarone, bleomycin,
nitrofurantoin
– social history
– occupational history
– exposure history
– Review of systems
• To exclude other causes of interstitial lung
disease.
28. CLINICAL FEATURES
SIGNS
• Evidence of respiratory distress
• fine bibasilar inspiratory crackles (Velcro
crackles).
• digital clubbing(25-50%)
• Cyanosis
• Aside features of pulm HTN/cor pulmonale, extra
pulmonary involvement does not occur with
idiopathic pulmonary fibrosis
32. DIAGNOSIS
• A Multidisciplinary Consensus Statement on the
Idiopathic Interstitial Pneumonias published by
the American Thoracic Society (ATS) and the
European Respiratory Society (ERS) in 2000
proposed specific major and minor criteria for
establishing the diagnosis of IPF.
• However, in 2011, new simplified and updated
criteria for the diagnosis and management of IPF
were published by the ATS, ERS, together with
the Japanese Respiratory Society (JRS) and Latin
American Thoracic Association (LATA)
33. DIAGNOSIS
Currently, a diagnosis of IPF requires:
• Exclusion of known causes of ILD, e.g., domestic
and occupational environmental exposures,
connective tissue disorders, or drug
exposure/toxicity
• The presence of a typical radiological Usual
Interstitial Pneumonia (UIP) pattern on HRCT.
• Specific combinations of HRCT and surgical lung
biopsy pattern in patients subjected to surgical
lung biopsy
34. IMAGING
High-resolution computed tomography
• an essential component of the diagnostic
pathway in IPF
• IPF is characterized by patchy, predominantly
peripheral, predominantly subpleural, and
bibasilar reticular opacities
• Subpleural honeycombing (< 5-mm round
translucencies with a density equal to that of
air) is also a common finding
36. IMAGING
• Ground-glass opacities can be found but are
less extensive than reticular abnormalities.
• Traction bronchiectasis could also be found
37. A patient with IPF and a confirmed histologic diagnosis of usual interstitial
pneumonia. Note the reticular opacities (red circle) distributed in both lung
bases and the minimal ground-glass opacities (blue circle)
38. High-resolution computed tomography scans
of the chest of a patient with IPF. The main
features are of a peripheral, predominantly
basal pattern of coarse reticulation with
honeycombing
39.
40. IMAGING
• Reticular opacities and honeycombing seen on
HRCT imaging correlates histologically with
fibrosis and honeycombing.
• The presence of subpleural honeycombing,
traction bronchiectasis, and thickened
interlobular septae increase the specificity of
HRCT for diagnosing idiopathic pulmonary
fibrosis
41. IMAGING
• Multiple studies have documented that the
accuracy of a confident diagnosis of usual
interstitial pneumonia made on the basis of
HRCT imaging findings by an experienced
observer exceeds 90%a
• a-Misumi S, Lynch DA. Idiopathic pulmonary fibrosis/usual interstitial pneumonia: imaging diagnosis, spectrum of
abnormalities, and temporal progression. Proc Am Thorac Soc. Jun 2006;3(4):307-14.
42. IMAGING
HRCT Criteria for UIP Pattern:
– UIP pattern requires all 4 features below.
• Subpleural, basal predominance
• Reticular abnormality
• Honeycombing with or without traction
bronchiectasis
• Absence of features listed as inconsistent with
UIP pattern
43. IMAGING
Inconsistent with UIP pattern requires any of the 7
features below.
– Upper or mid-lung predominance
– Peribronchovascular predominance
– Extensive ground-glass abnormality (extent greater than
reticular abnormality)
– Profuse micronodules (bilateral, predominantly upper
lobes)
– Discrete cysts (multiple, bilateral, away from areas of
honeycombing)
– Diffuse mosaic attenuation/air-trapping (bilaterally, in 3 or
more lobes)
– Consolidation in bronchopulmonary segment(s)/lobe(s)
44. IMAGING
Chest Radiography
• Virtually all patients with IPF have an
abnormal chest radiograph at the time of
diagnosis
• lacks diagnostic specificity for idiopathic
pulmonary fibrosis.
45. IMAGING
The typical findings :
• Peripheral reticular opacities (netlike linear
and curvilinear densities) predominantly at
the lung bases.
• Honeycombing (coarse reticular pattern) and
lower lobe volume loss can also be seen.
46. Chest radiograph of a patient with idiopathic
pulmonary fibrosis showing bilateral lower lobe
reticular opacities (red circles)
47. A chest radiograph of a patient with IPF. Note the
small lung fields and peripheral pattern of
reticulonodular opacification
48. OTHER TESTS
Pulmonary function testing
• Findings are nonspecific and should be used in
conjunction with clinical, radiologic, and
pathologic information to ensure an accurate
diagnosis
• Good for prognostication
49. • Ventilatory pattern – Restrictive
– Vital capacity, functional residual capacity, total lung
capacity, and forced vital capacity (FVC) all are
reduced
– Obstructive ventilatory defect, not common; if
present, may suggest the coexistence of COPD.
• Diffusion Capacity of Carbon monoxide (DLco) –
Reduced
– In IPF, reduced DLCO may precede the development of
abnormal lung volumes
50. 6-Minute walk testing (6MWT)
• marker of functional exercise capacity that is
being increasingly used in the initial and
longitudinal clinical assessment of patients
with idiopathic pulmonary fibrosis
51. • Markers of increased mortality
– Patients who have >10% decline in FVC (percent
predicted) over 6 months, have a 2.4-fold
increased risk of death.
– Baseline DLCO below 35% is correlated with
increased mortality.
– So also decline in DLCO greater than 15% over 1
year
– Desaturation below the threshold of 88% during
the 6MWT
52. Note:
• in patients who do not desaturate to less than
88% during a 6-minute walk test (6MWT), the
only strong predictor of mortality is a
progressive decline in FVC (>10% after 6 mo)
• in patients who desaturate to less than 88%
during a 6MWT, a progressive decline in DLCO
(>15% after 6 mo) is a strong predictor of
increased mortality
53. • Bronchoalveolar Lavage (BAL)
– not required for the diagnosis of IPF
– can be useful to exclude other alternative
diagnoses
– may demonstrate the presence of infection,
malignancy, alveolar proteinosis, eosinophilic
pneumonia, or occupational dusts.
BAL fluid neutrophilia has been demonstrated to
predict early mortality.
54. Diagnostic Value of Bronchoalveolar
Lavage in Interstitial Lung Disease
Condition Bronchoalveolar lavage finding
Sarcoidosis Lymphocytosis; CD4:CD8 ratio >3.5 most specific
of diagnosis
Hypersensitivity Pneumonitis Marked lymphocytosis (>50%)
Organizing Pneumonia Foamy macrophages; mixed pattern of increased
cells characteristic; decreased CD4:CD8 ratio
Eosinophilic lung disease Eosinophils > 25%
Diffuse alveolar bleeding Hemosiderin-laden macrophages, red blood cells
Diffuse alveolar damage – drug
toxicity
Atypical hyperplastic type II pneumocytes
Opportunistic infections Pneumocystis carinii, fungi, cytomegalovirus-
transformed cells
Lymphangitic carcinomatosis,
alveolar cell carcinoma, pulmonary
lymphoma
Malignant cells
55. Diagnostic Value of Bronchoalveolar
Lavage in Interstitial Lung DiseaseCondition BAL findings
Alveolar proteinosis Milky effluent, foamy macrophages and
lipoproteinaceous intraalveolar material (periodic
acid–Schiff stain–positive)
Lipoid pneumonia Fat globules in macrophages
Pulmonary Langerhans Cell
Histiocytosis
Increased CD1+ Langerhans cells, electron
microscopy demonstrating Birbeck granule in
lavaged macrophage (expensive and difficult to
perform)
Asbestos-related pulmonary
disease
Dust particles, ferruginous bodies
Berrylliosis Positive lymphocyte transformation test to
beryllium
Silicosis Dust particles by polarized light microscopy
Lipoidosis Accumulation of specific lipopigment in alveolar
macrophages
56. • Transthoracic Echocardiography – pulm HTN,
• ECG – pulmonary HTN
• Up to 30% of patients with IPF have positive
tests for ANA or rheumatoid factor; however,
these titers are generally not high.
– Presence of high titers may suggest the presence
of a connective-tissue disease.
• CRP, ESR – may be elevated (60-94%)
57. LUNG BIOPSY
• According to the updated 2011 guidelines, in the
absence of a typical UIP pattern on HRCT, a
surgical lung biopsy is required for confident
diagnosis
i.e, in patients with possible UIP pattern or
inconsistent with UIP pattern
• Histologic specimens for the diagnosis of IPF must
be taken at least in three different places and be
large enough that the pathologist can comment
on the underlying lung architecture
58. • Hence, surgical lung biopsy specimen are
obtained through either an open lung biopsy
or video-assisted thoracoscopic surgery (VATS)
59. HISTOLOGY
• The histopathological lesion associated with
idiopathic pulmonary fibrosis is -Usual interstitial
pneumonia(UIP).
• characterized by a heterogeneous, variegated
appearance with alternating areas of healthy
lung, interstitial inflammation, fibrosis, and
honeycomb change
• resulting in a patchwork appearance at low
magnification
60.
61. Photomicrograph of the histopathological appearances of usual interstitial
pneumonia. High-power magnification (on the right) shows a focus of
fibroblastic proliferation, close to an area of fibrosis within which a mild,
non-specific, chronic inflammatory cell infiltrate can be observed. In the
subpleural space, a typical honeycombing aspect can be recognized.
62. • Fibrosis predominates over inflammation in usual
interstitial pneumonia
• Fibroblastic foci represent microscopic zones of
acute lung injury and are randomly distributed
within areas of interstitial collagen deposition
and
• Consist of fibroblasts and myofibroblasts
arranged in a linear fashion within a pale-staining
matrix.
• they represent an important diagnostic criterion
63. UIP pattern requires all 4 criteria below.
• Evidence of marked fibrosis/architectural
distortion and/or honeycombing in a
predominantly subpleural/paraseptal distribution
• Presence of patchy involvement of lung
parenchyma by fibrosis
• Presence of fibroblast foci
• Absence of features against a diagnosis of UIP
suggesting an alternate diagnosis
64. • Probable UIP pattern requires the following:
– Evidence of marked fibrosis/architectural
distortion and/or honeycombing
– Absence of either patchy involvement or
fibroblastic foci, but not both
– Absence of features against a diagnosis of UIP
suggesting an alternate diagnosis
OR
– Honeycombing changes only
65. • Possible UIP pattern requires all 3 criteria.
– Patchy or diffuse involvement of lung parenchyma
by fibrosis, with or without interstitial
inflammation
– Absence of other criteria for UIP
– Absence of features against a diagnosis of UIP
suggesting an alternate diagnosis
66. • Not UIP pattern requires any of the 6 criteria.
– Hyaline membranes
– Organizing pneumonia
– Granulomas
– Marked interstitial inflammatory cell infiltrate
away from honeycombing
– Predominant airway centered changes
– Other features suggestive of an alternate
diagnosis
67. Diagnostic Considerations
• IPF
– possible UIP pattern on HRCT and
– UIP pattern or probable UIP pattern on surgical
lung biopsy
• Probable IPF
– possible UIP pattern on HRCT and
– possible UIP pattern or non-classifiable fibrosis on
surgical lung biopsy
68. • Possible IPF
– a pattern inconsistent with UIP on HRCT and
– UIP pattern on surgical lung biopsy
• Not IPF
– a pattern inconsistent with UIP on HRCT and
– probable UIP/possible UIP/ nonclassifiable fibrosis
on surgical lung biopsy
– Any pattern on HRCT associated with a surgical
lung biopsy finding of not UIP
69. DIFFERENTIAL DIAGNOSIS
• These are numerous. A few include
• Other Idiopathic Interstitial Pneumonias (IIPs)
– nonspecific interstitial pneumonia,
– cryptogenic organizing pneumonia,
– acute interstitial pneumonia
– lymphoid interstitial pneumonia
70. DIFFERENTIAL DIAGNOSIS
• Other causes of UIP pattern
– Systemic sclerosis/Scleroderma
– Hypersensitivity Pneumonitis
– Rheumatoid Arthritis
– Fibronodular Sarcoidosis
– Asbestosis
– Drug induced fibrosis
71. DIFFERENTIAL DIAGNOSIS
• Other causes of Ground Glass Appearance on
HRCT
– Heart Failure
– Non Specific Idiopathic Pneumonia (NSIP)
– Desquamative Interstitial Pneumonia
– Hypersensitivity Pneumonitis
73. TREATMENT
Non-pharmacologic
• Smoking cessation
• Diet: healthy diet/ideal body weight improves
QOL
• Long term Oxygen therapy – when SpO2<88%
or PaO2< 55mmHg
• Vaccination against influenza and
pneumoccocal infections
74. TREATMENT
Pharmacologic
• Novel approaches to treatment are being
developed based on the new theories of IPF
pathogenesis
• No optimal medical treatment of IPF is yet to
be identified
• Hence, risk-benefit ratio important.
75. TREATMENT
Antioxidants
• N-acetyl cysteine (NAC) – gluthathione
precursor
• Study of the Effects of High-Dose N-
Acetylcysteine (NAC) in IPF (IFIGENIA
Idiopathic Pulmonary Fibrosis International
Group Exploring N-Ace-tylcysteine I Annual)
– showed improvement in Dlco and VC over 12
months of follow up
76. TREATMENT
• Prednisone, Azathioprine, and N-acetylcysteine:
A Study That Evaluates Response in
IPF(PANTHER-IPF) however, worsened outcome,
and increased admission rate
Biological response modulators
• Etanercept (anti TNF-alpha) – no improvement
Endothelin receptor antagonists
• Bosentan showed no improvement in 6MWT over
placebo
77. TREATMENT
Phosphodiesterase inhibitors
• Sidenafil - no significant difference in the
6MWT
• However, statistically significant differences in
the change in dyspnea, PaO2, diffusing
capacity, and quality of life were noted.
78. TREATMENT
Tyrosine kinase inhibitors
• Imatinib mesylate: potent inhibitor of lung
fibroblast-myofibroblast transformation and
proliferation, through inhibition of platelet-
derived growth factor and transforming
growth factor-β signaling – showed no
significant improvement in lung function over
placebo
79. TREATMENT
Antifibrotic agents
• Pirfenidone(Esbriet): a novel compound with
combined anti-inflammatory, antioxidant, and
antifibrotic effects – first approved in Japan
• Approved by USA FDA in Oct 15 2014
• Colchicine: no improvement in clinical
outcome
Anticoagulant: worsened outcome
80. TREATMENT
Surgical
• Lung transplantation – definitive treatment
– Any patient diagnosed with IPF or probable IPF should
be referred for lung transplantation evaluation,
regardless of the vital capacity
• Indication for listing
– DLCO <39% predicted,
– 10% or greater decrement in FVC during 6 months of
follow-up,
– decrease in pulse oximetry below 88% during a 6MWT
– or honeycombing on HRCT imaging
81. COMPLICATIONS
Acute exacerbation of IPF (AE-IPF)
• Commonest/most dreaded
• Worsens prognosis
• Rate – 10-57%
• Usually secondary to infections, pulmonary
embolism, or pneumothorax
82. COMPLICATIONS
Diagnostic criteria for an AE-IPF:
• Previous or concurrent diagnosis of idiopathic pulmonary
fibrosis
• Unexplained worsening or development of dyspnea within
30 days
• HRCT scan with new bilateral ground-glass abnormality
and/or consolidation superimposed on a background
reticular or honeycomb pattern consistent with a usual
interstitial pneumonia pattern
• Worsening hypoxemia from a known baseline arterial blood
gas measurement
• No evidence of pulmonary infection by endotracheal
aspiration or BAL
84. PROGNOSIS
• Prognosis is poor
• 5yr survival rate – 20-40%
Poor prognostic factors
– >10% decline in FVC (% predicted) over 6 months
– DLCO <35%
– A decline in DLCO >15% over 1 year
– Desaturation below the threshold of 88% during the
6MWT
– Progressive decline in DLCO (>15% after 6 mo)
– BAL fluid neutrophilia
– Male sex
– Age >65
85. CONCLUSION
• IPF is a chronic progressive fibrosing IP
• Aetiology is unknown
• It’s uncommon but invariably fatal
• Bears semblance to a host of other disease entities
• Diagnosis relies on the clinician integrating the clinical,
laboratory, radiologic, and/or pathologic features to
make a clinical-radiologic-pathologic correlation that
supports its diagnosis.
• No proven effective medical therapy save lung
transplantation.
86. REFERENCES
• Raghu G, Collard HR, Egan JJ, Martinez FJ, Behr J,
Brown KK. An Official ATS/ERS/JRS/ALAT Statement:
Idiopathic Pulmonary Fibrosis: Evidence-based
Guidelines for Diagnosis and Management. Am J Respir
Crit Care Med. Mar 15 2011;183(6):788-824.].
• American Thoracic Society/European Respiratory
Society International Multidisciplinary Consensus
Classification of the Idiopathic Interstitial Pneumonias.
This joint statement of the American Thoracic Society
(ATS), and the European Respiratory Society (ERS) was
adopted by the ATS board of directors, June 2001 and
by the ERS Executive Committee, June 2001. Am J
Respir Crit Care Med. Jan 15 2002;165(2):277-304.
87. REFERENCES
• du Bois RM, Weycker D, Albera C, Bradford
WZ, Costabel U, Kartashov A, et al. Forced vital
capacity in patients with idiopathic pulmonary
fibrosis: test properties and minimal clinically
important difference. Am J Respir Crit Care
Med. Dec 15 2011;184(12):1382-9
• Wikipedia online
• Medscape online
• Harrison’s textbook of clinical medicine